Transcriptional Behavior of Regulatory T Cells Predicts IBD Patient Responses to Vedolizumab Therapy

Abstract

Background Inflammatory bowel disease (IBD) involves chronic T cell–mediated inflammatory responses. Vedolizumab (VDZ), a monoclonal antibody against α4β7 integrin, inhibits lymphocyte extravasation into intestinal mucosae and is effective in ulcerative colitis (UC) and Crohn’s disease (CD). Aim We sought to identify immune cell phenotypic and gene expression signatures that related to response to VDZ. Methods Peripheral blood (PBMC) and lamina propria mononuclear cells (LPMCs) were analyzed by flow cytometry and Cytofkit. Sorted CD4 + memory (Tmem) or regulatory T (Treg) cells from PBMC and LPMC were analyzed by RNA sequencing (RNA-seq). Clinical response (≥2-point drop in partial Mayo scores [UC] or Harvey-Bradshaw index [CD]) was assessed 14 to 22 weeks after VDZ initiation. Machine-learning models were used to infer combinatorial traits that predicted response to VDZ. Results Seventy-one patients were enrolled: 37 received VDZ and 21 patients remained on VDZ >2 years. Fourteen of 37 patients (38%; 8 UC, 6 CD) responded to VDZ. Immune cell phenotypes and CD4 + Tmem and Treg transcriptional behaviors were most divergent between the ileum and colon, irrespective of IBD subtype or inflammation status. Vedolizumab treatment had the greatest impact on Treg metabolic pathways, and response was associated with increased expression of genes involved in oxidative phosphorylation. The strongest clinical predictor of VDZ efficacy was concurrent use of thiopurines. Mucosal tissues offered the greatest number of response-predictive biomarkers, whereas PBMC Treg-expressed genes were the best predictors in combinatorial models of response. Conclusions Mucosal and peripheral blood immune cell phenotypes and transcriptional profiles can inform VDZ efficacy and inform new opportunities for combination therapies.

High-dimensional single-cell analysis identifies cellular signatures associated with response to vedolizumab therapy in ulcerative colitis

“…Indeed, it has been previously described that an aberrant expression pro le of gut mucosal and peripheral blood Tregs is associated with VDZ non-response, 25 and we observe that this stems from an impaired cellular crosstalk with their innate counterparts -in ammatory monocytes. Furthermore, we show that a speci c (sub)phenotype of in ammatory broblasts promotes VDZ non-response: unlike the IL-11 expressing broblasts of the GIMATS module, in ammatory broblasts of VDZ non-response module execute their immunomodulatory functions via CXCL12.…”

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis

“…Here we confirm that VDZ shifts ɑ4β7 + cells from the colon to the circulation for most cell types, but this results in a small net change in tissue cell frequency for most cell subsets. Multiple studies have investigated the effect of VDZ on T cell subsets, in general supporting models where pathogenic effector T cell subsets are excluded more efficiently than regulatory T cell subsets 6–8,45 . Our data do not exclude any of these observations, but rather add that VDZ is correlated with alterations in the abundance and expression of circulating and intestinal MNP subsets, which likely contributes to a reduction in tissue inflammation.…”

Identification of master regulator genes controlling pathogenic CD4+ T cell fate in inflammatory bowel disease through transcriptional network analysis

“…Additionally, the expression profile of peripheral blood Treg was evaluated in IBD patients undergoing vedolizumab treatment, a monoclonal antibody that blocks α4β7 integrin, thus dampening the recruitment of lymphocyte into the intestine. Interestingly, the therapeutic antibody treatment demonstrated a significant impact on Treg metabolic pathways, particularly oxidative phosphorylation, which is associated with better bioenergetic fitness and higher Treg suppressive function and persistence 49 .…”